Process for preparing certain phenyl urea compounds

ABSTRACT

This invention relates to a process for making certain phenyl urea compounds by using a Lewis acid to effect the ring opening of a benzoxazolinone by an amine.

SCOPE OF THE INVENTION

This invention relates to a process for making certain phenyl urea compounds. The end-product phenyl urea compounds are useful in treating IL-8, GROα, GROGβ, GROγ and NAP-2 mediated diseases.

BACKGROUND OF THE INVENTION

Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1a, IL-1b or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al, J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter, et al, Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al, J. Immunol. 148, 3216 (1992).

There is a need for treatment in this field, for compounds which are capable of binding to the IL-8 α or β receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding. Such compounds have been disclosed in published patent applications exemplified by the likes of PCT/US96/13632) published Aug. 21, 1997 as WIPO No. WO97/29743.

Specifically this invention provides a method for synthesising N-[2-hydroxy-4-cyanophenyl]-N′-[2-bromophenyl]urea, a compound disclosed in PCT application serial number PCT/US96/13632, published Aug. 21, 1997 an WIPO No. WO97/29743 and related compounds.

SUMMARY OF THE INVENTION

In a first aspect this invention covers a process for making a compound of Formula

wherein

X is oxygen;

R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less.

R1 is independently selected from hydrogen; halogen; nitro; cyano; C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl; C₂₋₁₀ alkenyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀alkoxy; azide; S(O)_(t)R₄; (CR₈R₈)q S(O)_(t)R₄; hydroxy; hydroxy substituted C₁₋₄alkyl; aryl; aryl C₁₋₄ alkyl; aryl C₂₋₁₀ alkenyl; aryloxy; aryl C₁₋₄ alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C₂₋₁₀ alkenyl; heteroaryl C₁₋₄ alkyloxy; heterocyclic, heterocyclic C₁₋₄alkyl; heterocyclicC₁₋₄alkyloxy; heterocyclicC₂₋₁₀ alkenyl; (CR₈R₈)q NR₄R₅; (CR₈R₈)q C(O)NR₄R₅; C₂₋₁₀ alkenyl C(O)NR₄R₅; (CR₈R₈)q C(O)NR₄R₁₀; S(O)₃H; S(O)₃R₈; (CR₈R₈)q C(O)R₁₁; C₁₋₁₀ alkenyl C(O)R₁₁: C₂₋₁₀ alkenyl C(O)OR₁₁; (CR₈R₈)q C(O)OR₁₁; (CR₈R₈)q OC(O)R₁₁; (CR₈R₈)qNR₄C(O)R₁₁; (CR₈R₈)q C(NR₄)NR₄R₅; (CR₈R₈)q NR₄C(NR₅)R₁₁, (CR₈R₈)q S(O)₂NR₄R₅, or two R₁ moieties together may form a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;

q is 0 or an integer having a value of 1 to 10;

t is 0 or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

R4 and R₅ are independently, optionally substituted C₁₋₄ alkyl, optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl, optional v substituted heteroaryl, optionally substituted heteroaryl C₁₋₄alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, or R₄ and R₅ together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N or S;

Y is R₁;

q is 0 or an integer having a value of 1 to 10;

m is an integer having a value of 1 to 3;

R₆ and R₇ are independently hydrogen or a C₁₋₄ alkyl group, or R₆ and R₇ together with the nitrogen to which they are attached form a 5 to 7 member ring which ring, may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;

R₈ is hydrogen or C₁₋₄ alkyl;

R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈;

R₁₁ is hydrogen, optionally substituted C₁₋₄ alkyl, optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC₁₋₄alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC₁₋₄alkyl,

R₁₂ is hydrogen, C₁₋₁₀ alkyl, optionally substituted aryl or optionally substituted arylalkyl;

R₁₃ is suitably C₁₋₄ alkyl, aryl, aryl C₁₋₄alkyl heteroaryl, heteroarylC₁₋₄alkyl, heterocyclic, or heterocyclicC₁₋₄alkyl;

R_(b) is NR₆R₇, alkyl, aryl, aryl C₁₋₄ alkyl, aryl C₂₋₄ alkenyl, heteroaryl, heteroaryl C₁₋₄ alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, heterocyclic C₁₋₄ alkyl, heterocyclic C₂₋₄ alkenyl, or camphor, all of which groups may be optionally substituted;

wherein said process comprises reacting a compound of Formula (A)

where R₁ is the same as defined in Formula I with a nucleophile illustrated by the amine of Formula (B)

where Y is the same as defined above in the presence of a Lewis acid to open the oxazolinone ring of Formula (A) to form the urea of Formula (I).

In a second aspect, this invention relates to a process for making a compound of Formula (I) as described above wherein the process comprises treating a benzoxazolinone of Formula (D)

with a halogen in the presence of an acid to form a compound of Formula (C);

then treating Formula C with CuCN to form a compound of Formula (A1), and

reacting Formula A1 with a nucleophile illustrated by Formula (B)

where Y is the same as defined in Formula I in the presence of a Lewis acid to open the oxazolinone ring of Formula (A) and form the compound of Formula (I) where R is OH and R₁ is CN.

The preferred compounds which can be synthesised by these methods and using these inter mediates are those where R₁ is halogen, cyano, nitro, CF₃, C(O)NR₄R₅, alkenyl C(O)NR₄R₅, C(O) R₄R₁₀, alkenyl C(O)OR₁₂, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR₄R₅, and preferably one of R₄ or R₅ is phenyl. A preferred ring substitution for R₁ is in the 4-position of the phenyl ring.

Preferably R₁ is nitro, halogen, cyano, trifluoromethyl group, or C(O)NR₄R₅.

Y is preferably a halogen, C₁₋₄ alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR₄R₅. thioC₁₋₄alkyl, thioaryl halosubstituted alkoxy, optionally substituted C₁₋₄ alkyl, or hydroxy alkyl, Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2′-position or 2′-, 31-position. 25 While Y may be substituted in any of the 5 ring positions, preferably when R is OH, or SH, Y is preferably mono-substituted in the 2′-position or 3′-position, with the 4′-preferably being unsubstituted. If the ring is disubstituted, when R is OH or SH substituents are preferably in the 2′ or 3′ position of a monocyclic ring. While both R₁ and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are substituted.

Preferred compounds include:

N-[2-hydroxy-4-cyanophenyl]-N′-[2-bromophenyl] urea

N-[2-hydroxy-4-cyanophenyl]-N′-[2,3-dichlorophenyl] urea

N-(2-hydroxy-4-cyanophenyl)-N′-(2-(4-pyridylmethyloxy)phenyl)urea, and

N-(2-hydroxy-4-cyanophenyl)-N′-(2-chlorophenyl)urea.

SPECIFIC EMBODIMENTS OF THE INVENTION

Reaction Scheme 1 details in graphical form the process and representative intermediates which are the subject of this invention.

The benzoxazolinone starting material is commercially available (formula 1-1). See for example Aldrich. It is halogenated (formula 1-2) by mixing it with a solution of an organic acid and a the alkali metal salt of that acid in a molar amount about equal to that of the benzoxazolinone and treating that mixture or solution with the halogen. Glacial acetic acid and its sodium salt are the preferred organic acid/salt combination. In the case of the illustrated benzoxazolinone, a suspension forms. That suspension is cooled to below ambient temperature, somewhere between 0-20° C. and then bromine is added slowly; a slight molar excess of bromine with reference to the benzoxazolinone is preferred. This mixture is stirred at ambient temperature for a period sufficient to effect the reaction, usually about 12 hours to overnight. No special conditions are required to work up the halogenated product.

The nitrile of formula 1-3 is prepared by treating the halogenated benzoxazolinone with CuCN at a moderately elevated temperature under an inert gas in a polar solvent such as dimethyl formamide, N-methyl pyrrolidinone or dimethyl sulfoxide. As illustrated herein, the benzoxazolinone is added to the solvent followed by the CuCN (in about a 75% molar excess). This mixture is heated to a temperature which is in the range of 120-175° C. The reaction is carried out under an inert gas, preferably nitrogen. The reaction mixture is heated to the noted temperature range for about 4-8 hours. Then the reaction is cooled to about 100° C. a 3 to 4-fold molar excess of NaCN is added, and the resulting suspension is stirred for a couple of more hours at ambient temperature. No special workup is required to recover the nitrile.

The urea (formula 1-4) is made by treating the benzoxazolinone with an amine in the presence of a Lewis acid. Exemplary Lewis acids include Ti, Al or Sn (TiCl₄, tributyltin chloride, and diethylaluminum). The nitrile of Formula A or A1 is added to a mixture of the salt of the amine and a Lewis acid in a non-polar solvent; 2-bromoaniline is illustrated in Scheme 1. About a 5-7 molar excess of the amine is used and about 2-3 molar excess of the Lew is acid is used. This mixture is refluxed for several hours, for example 5-6 hours. Isolating the product involves cooling the reaction mixture to about 0° C., partitioning with aqueous mineral acid/organic solvent and filtering the organic layer through SiO₂.

The following examples are given to illustrate the invention but are not to be taken as limiting what is covered by the claims.

EXAMPLES Example 1 6-Bromo-2(3H)-benzoxazolone

To a solution of glacial acetic acid (1500 ml) was added sodium acetate (222 g, 2.70 mole) and 2-benzoxazolinone (300 g, 2.22 mole). The suspension was cooled to 15° C. bromine (118 ml, 2.29 mole) added dropwise over 1 h and the mixture stirred for 12 h at ambient temperature. The solids were then filtered, washed with H₂O (3×500 ml) and dried under vacuum to give the title compound as a white solid (374 g, 89.7%): mp 186.0-187.0° C.: ¹H NMR (DMSO-d₆) δ 11.8 (s, 1 H), 7.6 (s, 1 H), 7.3 (d, J=8.0 Hz, 1 H), 7.0 (d, J=8.0 Hz, 1 H).

Example 2 2,3-Dihydro-4-hydroxy-2-oxo-6-benzoxazolecarbonitrile

To a solution of DMF (110 ml) was added 6-bromo-2(3H)-benzoxazolone (50 g, 0.234 mole) and CuCN (89.6 g, 0.398 mole) and the mixture heated to 150° C. for 6 h under nitrogen. The reaction was then cooled to 100° C., H₂O (200 ml) and NaCN (36 g, 0.734 mole) added, the suspension stirred for 2 h at ambient temperature and partitioned with EtOAc at 70° C. The organic phase was washed with H₂O (2×150 ml) and concentrated in vacuo to give the title compound as a tan solid (33.2 g, 88.5%); mp>220° C.; ¹H NMR (DMSO-d₆) δ 7.8 (s, 1 H), 7.6 (d, J=8.0 Hz, 1 H), 7.2 (d, J=8.0 Hz, 1 H).

Example 3 N-(2-Bromophenyl)-N′-(2-hydroxy-4-cyanophenyl) Urea

A solution of 2-bromoanaline (6.8 g, 39.5 mmol) in toluene (10 mL)/dichloromethane (10 mL) was added to sodium hydride (60%, 1.65 g, 41.0 mmol) and the mixture was warmed to 60° C. for 45 minutes. The mixture was cooled to 5° C. and TiCl₄ (1.37 mL, 12.6 mmol) was added over 15 minutes. 2,3-Dihydro-4-hydrozy-2-oxo-6-benzoxazole carbonitrile (1.0 g, 6.0 mmol) was added and the mixture heated at reflux for 5.5 hours. The reaction was cooled to 0° C., partitioned with 15% HCl (25 ml) and EtOAc (150 ml), and the organic phase filtered through SiO₂ (50 g). The filtrate was concentrated in vacuo to give a brown solid comprising the title product (0.7 g, 58.6%). 

What is claimed is:
 1. A process for making a compound of Formula

wherein X is oxygen; R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less; R₁ is independently selected from hydrogen; halogen; nitro; cyano; C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl; C₂₋₁₀ alkenyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy; azide; S(O)_(t)R₄; (CR₈R₈)q S(O)_(t)R₄; hydroxy; hydroxy substituted C₁₋₄ alkyl, aryl; aryl C₁₋₄ alkyl; aryl C₂₋₁₀ alkenyl; aryloxy; aryl C₁₋₄ alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C₂₋₁₀ alkenyl; heteroaryl C₁₋₄ alkyloxy; heterocyclic, heterocyclic C₁₋₄alkyl; heterocyclicC₁₋₄alkyloxy; heterocyclicC₂₋₁₀ alkenyl; (CR₈R₈)q NR₄R₅; (CR₈R₈)q C(O)NR₄R₅; C₂₋₁₀ alkenyl C(O)NR₄R₅; (CR₈R₈)q C(O)NR₄R₁₀; S(O)₃H; S(O)₃R₈; (CR₈R₈)q C(O)R₁₁; C₂₋₁₀ alkenyl C(O)R₁₁; C₂₋₁₀ alkenyl C(O)OR₁₁; (CR₈R₈)q C(O)OR₁₁; (CR₈R₈)q OC(O)R₁₁; (CR₈R₈)qNR₄C(O)R₁₁; (CR₈R₈)q C(NR₄)NR₄R₅; (CR₈R₈)q NR₄C(NR₅)R₁₁, (CR₈R₈)q S(O)₂NR₄R₅, or two R₁ moieties together may form a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted; q is 0 or an integer having a value of 1 to 10; q is 0 or an integer having a value of 1 to 10; t is 0 or an integer having a value of 1 or 2; s is an integer having a value of 1 to 3; R₄ and R₅ are independently optionally substituted C₁₋₄ alkyl, optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C₁₋₄alkyl, heterocyclic, heterocyclic C₁₋₄ alkyl, or R₄ and R₅ together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N or S; Y is R₁; q is 0 or an integer having a value of 1 to 10; m is an integer having a value of 1 to 3; R₆ and R₇ are independently hydrogen or a C₁₋₄ alkyl group, or R₆ and R₇ together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur; R₈ is hydrogen or C₁₋₄ alkyl; R₁₀ is C₁₋₁₀ alkyl C(O)₂R₈; R₁₁ is hydrogen, optionally substituted C₁₋₄ alkyl, optionally substituted aryl, optionally substituted aryl C₁₋₄alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC₁₋₄alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC₁₋₄alkyl; R₁₂ is hydrogen, C₁₋₁₀ alkyl, optionally substituted aryl or optionally substituted arylalkyl; R₁₃ is suitably C₁₋₄ alkyl, aryl, aryl C₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclic, or heterocyclicC₁₋₄alkyl; R_(b) is NR₆R₇, alkyl, aryl, aryl C₁₋₄ alkyl, aryl C₂₋₄ alkenyl, heteroaryl, heteroaryl C₁₋₄ alkyl, heteroarylC₂₋₄ alkenyl, heterocyclic, heterocyclic C₁₋₄ alkyl, heterocyclic C₂₋₄ alkenyl, or camphor, all of which groups may be optionally substituted; wherein said process comprises reacting a compound of Formula (A)

with a nucleophile illustrated by the amine of Formula (B)

in the presence of a Lewis acid to open the oxazolinone ring of Formula (A) to form the urea of Formula (I).
 2. The process of claim 1 wherein the Lewis acid is TiCl₄, tributyltin chloride, or diethylaluminum.
 3. The process of claim 1 wherein the product is a compound of Formula I where R₁ is halogen, cyano, nitro, CF₃, C(O)NR₄R₅, alkenyl C(O)NR₄R₅, C(O) R₄R₁₀, alkenyl C(O)OR₁₂, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR₄R₅, and preferably one of R₄ or R₅ is phenyl; Y is halogen, C₁₋₄ alkoxy, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR₄R₅, thioC₁₋₄alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C₁₋₄ alkyl, or hydroxy alkyl; and R is OH.
 4. The process of claim 1 wherein Y is halogen.
 5. The process of claim 1 wherein R₁ is CN.
 6. The process of claim 3 where the Lewis acid is TiCl₄.
 7. The process of claim 6 wherein the product is N-[2-hydroxy-4-cyanophenyl]-N′-[2-bromophenyl] urea N-[2-hydroxy-4-cyanophenyl]-N′-[2.3-dichlorophenyl] urea N-(2-hydroxy-4-cyanophenyl)-N′-(2-(4-pyridylmethyloxy)phenyl)urea, or N-(2-hydroxy-4-cyanophenyl)-N′-(2-chlorophenyl)urea.
 8. A process for making a compound of Formula (I) according to claim 1 wherein the process comprises treating a benzoxazolinone of Formula (D)

with a halogen in the presence of an acid to form a compound of Formula (C);

then treating Formula C with CuCN to form a compound of Formula (A1), and

reacting Formula (A1) with a nucleophile illustrated by Formula (B)

in the presence of a Lewis acid to open the oxazolinone ring of the compound of Formula (A) and form the compound of Formula (I) where R is OH, R₁ is CN and Y is hydrogen; halogen; nitro; cyano; C₁₋₁₀ alkyl; halosubstituted C₁₋₁₀ alkyl; C₂₋₁₀ alkenyl; C₁₋₁₀ alkoxy; halosubstituted C₁₋₁₀ alkoxy; azide; S(O)_(t)R₄; (CR₈R₈)q S(O)_(t)R₄; hydroxy; hydroxy substituted C₁₋₄alkyl; aryl; aryl C₁₋₄ alkyl; aryl C₂₋₁₀ alkenyl; aryloxy; aryl C₁₋₄ alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C₂₋₁₀ alkenyl; heteroaryl C₁₋₄ alkyloxy; heterocyclic, heterocyclic C₁₋₄alkyl; heterocyclicC₁₋₄alkyloxy; heterocyclicC₂₋₁₀ alkenyl; (CR₈R₈)q NR₄R₅; (CR₈R₈)q C(O)NR₄R₅; C₂₋₁₀ alkenyl C(O)NR₄R₅; (CR₈R₈)q C(O)NR₄R₁₀; S(O)₃H; S(O)₃R₈; (CR₈R₈)q C(O)R₁₁; C₂₋₁₀ alkenyl C(O)R₁₁; C₂₋₁₀ alkenyl C(O)OR₁₁; (CR₈R₈)q C(O)OR₁₁; (CR₈R₈)q OC(O)R₁₁; (CR₈R₈)qNR₄C(O)R₁₁; (CR₈R₈)q C(NR₄)NR₄R₅; (CR₈R₈)q NR₄C(NR₅)R₁₁, (CR₈R₈)q S(O)₂NR₄R₅, or two R₁ moieties together may form a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted. 